Compositions Containing Ibrutinib

ABSTRACT

Discussed herein are pharmaceutical compositions containing Ibrutinib and processes for preparing them. The compositions may be utilized in the treatment of a variety of conditions including, without limitation, B-cell proliferative disorders such as non-Hodgkin lymphoma (diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma or burkitt lymphoma), Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, lymphoma, or leukemia. These compositions are designed for oral ingestion. The compositions are contained within a capsule such as a standard or sprinkle or in a liquid formulation such as a suspension. In one embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In another embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide, and water.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/602,989, filed May 23, 2017, which is a divisional of U.S. patentapplication Ser. No. 15/092,195 filed Apr. 6, 2016, which claims thebenefit of U.S. Provisional Application No. 62/143,659, filed Apr. 6,2015, the entireties of which are incorporated by reference.

TECHNICAL FIELD

This invention relates to compositions containing Ibrutinib and methodsfor using same.

BACKGROUND

Targeted therapy involves identifying specific differences betweencancer cells and normal cells. These differences are used to create atargeted therapy to attack the cancer cells without damaging the normalcells, thus leading to fewer side effects. Differences exist between thevarious types of targeted therapy but all interfere with the ability ofthe cancer cell to grow, divide, repair and/or communicate with othercells.

Ibrutinib is an anticancer drug targeting B-cell malignancies. Ibrutinibblocks signals that stimulate malignant B cells to grow and divideuncontrollably. It was approved by the US FDA in November 2013 for thetreatment of mantle cell lymphoma and in February 2014 for the treatmentof chronic lymphocytic leukemia. It is an orally-administered, selectiveand covalent inhibitor (IC₅₀=0.46 nM) of the enzyme Bruton's tyrosinekinase (BTK) via a covalent bond to the cysteine residue Cys-481 in theBTK active site. BTK is a signaling molecule of the B-cell antigenreceptor (BCR) and cytokine receptor pathways. The BCR pathway isimplicated in several B-cell malignancies, including MCL and B-cell CLL.Ibrutinib is marked in the US in oral capsule form (Imbruvica™).

What is needed in the art are alternate formulations containingIbrutinib.

SUMMARY OF THE INVENTION

In one aspect, pharmaceutical compositions are provided comprisingIbrutinib, a salt, prodrug, or metabolite thereof, microcrystallinecellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesiumstearate. In one embodiment, the composition contains about 40 to about45% by weight of Ibrutinib.

In another aspect, pharmaceutical compositions are provided comprising(i) about 40 to about 45% by weight of Ibrutinib; (ii) about 44 to about47% by weight of microcrystalline cellulose; (iii) about 6 to about 8%by weight of croscarmellose sodium; (iv) about 1 to about 5% by weightof sodium lauryl sulfate; and (v) about 0.2 to about 0.3% by weight ofmagnesium stearate.

In a further aspect, pharmaceutical compositions are provided comprising(i) about 140 mg of Ibrutinib; (ii) about 151 mg of microcrystallinecellulose; (iii) about 23 mg of croscarmellose sodium; (iv) about 14 mgof sodium lauryl sulfate; and (v) about 1.6 mg of magnesium stearate.

In still another aspect, pharmaceutical compositions are providedcomprising (i) about 50 mg of Ibrutinib; (ii) about 54 mg ofmicrocrystalline cellulose; (iii) about 8 mg of croscarmellose sodium;(iv) about 5 mg of sodium lauryl sulfate; and (v) about 0.6 mg ofmagnesium stearate.

In yet a further aspect, capsules or sachets are provided comprising atleast one of the pharmaceutical compositions described herein. Incertain embodiments, the capsule is a standard or sprinkle.

In another aspect, pharmaceutical compositions are provided comprisingIbrutinib, a salt, prodrug, or metabolite thereof, microcrystallinecellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose,citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodiummethyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate,concentrated hydrochloric acid, sodium hydroxide, and water.

In still a further aspect, pharmaceutical compositions are providedcomprising (i) about 70 mg/mL of Ibrutinib; (ii) about 13 mg/mL of acombination of microcrystalline cellulose and carboxymethylcellulosesodium; (iii) about 2.5 mg/mL of hydroxypropylmethylcellulose; (iv)about 1.5 mg/mL of citric acid monohydrate; (v) about 1.4 mg/mL ofdisodium hydrogen phosphate; (vi) about 1 mg/mL of sucralose; (vii)about 1 mg/mL of sodium methyl parahydroxybenzoate; and (viii) about 0.6mg/mL of sodium ethyl parahydroxybenzoate.

In other aspects, pharmaceutical compositions are provided comprising(i) about 40 mg/mL of Ibrutinib; (ii) about 14 mg/mL of a combination ofmicrocrystalline cellulose and carboxymethylcellulose sodium; (iii)about 1 mg/mL of hydroxypropylmethylcellulose; (iv) about 1.5 mg/mL ofcitric acid monohydrate; (v) about 1.4 mg/mL of disodium hydrogenphosphate; (vi) about 0.5 mg/mL of sucralose; (vii) about 1.4 mg/mL ofsodium methyl parahydroxybenzoate; and (viii) about 0.6 mg/mL of sodiumethyl parahydroxybenzoate.

In yet another aspect, methods for treating a B-cell proliferativedisorder are provided comprising the steps of administering at least onepharmaceutical composition described herein to a subject in needthereof. In certain embodiments, the B-cell proliferative disorder is anon-Hodgkin lymphoma, Waldenstrom macroglobulinemia, plasma cellmyeloma, or chronic lymphocytic leukemia.

In a further aspect, methods for treating a lymphoma are providedcomprising administering at least one composition described herein to asubject in need thereof.

In another aspect, methods of treating a leukemia are providedcomprising administering at least one composition described herein to asubject in need thereof.

In still a further aspect, methods for treating mantle cell lymphoma ina subject who has already received at least one prior therapy for mantlecell lymphoma are provided comprising administering at least onecomposition described herein to the subject once per day.

In a further aspect, the treatment methods herein involve use of asprinkle capsule that is open to facilitate sprinkling of the capsule'scontents into food or a beverage. In one embodiment, the beverage iswater. In another embodiment, the food is a soft food. Capsule contentscan also be administered via feeding tube after spending into suitablevehicle such as water, milk or other common beverages. Please note thesuspension formulation can also be administered via feeding tube.

In yet another aspect, processes for preparing compositions describedherein are provided comprising (a) blending microcrystalline cellulose,a first portion of sodium lauryl sulfate, and a first portion ofcroscarmellose sodium; (b) blending the product of step (a) with a firstportion of Ibrutinib; (c) blending the product of step (b) with a secondportion of Ibrutinib; (d) blending the product of step (c) with a firstportion of magnesium stearate; (e) roller compacting the product of step(d); (f) milling the ribbons produced in step (e); (g) blending thegranules produced in step (e) with a second portion of sodium laurylsulfate and croscarmellose sodium; and (h) blending the product of step(g) with a second portion of magnesium stearate. In one embodiment, theprocess further includes (i) adding the product of step (h) to acapsule.

In a further aspect, processes for preparing compositions describedherein are provided comprising (a) mixing water, microcrystallinecellulose croscarmellose sodium; (b) mixing water withhydroxypropylmethylcellulose; (c) mixing the product of step (b) withIbrutinib; (d) mixing the product of steps (a) and (c); (e) mixing theproduct of the step (d) with sucralose; (f) mixing the product of step(e) with sodium methyl parahydroxybenzoate and sodium ethylparahydroxybenzoate; (g) mixing the product of step (f) with monohydratecitric acid; and (h) mixing the product of step (g) with anhydrousdisodium hydrogen phosphate. In one embodiment, the process furtherincludes (i) adjusting the pH of the product of step (h) to a pH ofabout 6. In another embodiment, the processes further include addingwater to the product of step (h) or (i). In a further aspect, theprocesses further include adding the composition to a vial.

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

The present application is further understood when read in conjunctionwith the appended drawings. For the purpose of illustrating the subjectmatter, there are shown in the drawings exemplary embodiments of thesubject matter; however, the presently disclosed subject matter is notlimited to the specific compositions, methods, devices, and systemsdisclosed. In addition, the drawings are not necessarily drawn to scale.

FIG. 1 provides a process flow diagram for preparing capsules containingIbrutinib.

FIG. 2 provides a process flow diagram for preparing liquid formulationscontaining Ibrutinib.

FIG. 3 provides a process flow diagram for a large scale preparation ofa liquid formulation containing Ibrutinib.

DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS

The present invention may be understood more readily by reference to thefollowing description taken in connection with the accompanying Figuresand Examples, all of which form a part of this disclosure. It is to beunderstood that this invention is not limited to the specific products,methods, conditions or parameters described and/or shown herein, andthat the terminology used herein is for the purpose of describingparticular embodiments by way of example only and is not intended to belimiting of any claimed invention. Similarly, unless otherwise stated,any description as to a possible mechanism or mode of action or reasonfor improvement is meant to be illustrative only, and the inventionherein is not to be constrained by the correctness or incorrectness ofany such suggested mechanism or mode of action or reason forimprovement. Throughout this text, it is recognized that thedescriptions refer both to the features and methods of making and usingthe compositions described herein.

In the present disclosure the singular forms “a”, “an” and “the” includethe plural reference, and reference to a particular numerical valueincludes at least that particular value, unless the context clearlyindicates otherwise. Thus, for example, a reference to “a material” is areference to at least one of such materials and equivalents thereofknown to those skilled in the art, and so forth.

When a value is expressed as an approximation by use of the descriptor“about” or “substantially” it will be understood that the particularvalue forms another embodiment. In general, use of the term “about” or“substantially” indicates approximations that can vary depending on thedesired properties sought to be obtained by the disclosed subject matterand is to be interpreted in the specific context in which it is used,based on its function. The person skilled in the art will be able tointerpret this as a matter of routine. In some cases, the number ofsignificant figures used for a particular value may be one non-limitingmethod of determining the extent of the word “about” or “substantially”.In other cases, the gradations used in a series of values may be used todetermine the intended range available to the term “about” or“substantially” for each value. Where present, all ranges are inclusiveand combinable. That is, references to values stated in ranges includeevery value within that range.

When a list is presented, unless stated otherwise, it is to beunderstood that each individual element of that list and everycombination of that list is to be interpreted as a separate embodiment.

For example, a list of embodiments presented as “A, B, or C” is to beinterpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A orC,” “B or C,” or “A, B, or C.”

It is to be appreciated that certain features of the invention whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.That is, unless obviously incompatible or excluded, each individualembodiment is deemed to be combinable with any other embodiment(s) andsuch a combination is considered to be another embodiment. Conversely,various features of the invention that are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any sub-combination. It is further noted that the claims may bedrafted to exclude any optional element. As such, this statement isintended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.Finally, while an embodiment may be described as part of a series ofsteps or part of a more general structure, each said step may also beconsidered an independent embodiment in itself.

The term “subject” as used herein refers to an animal being treated fora condition requiring Ibrutinib. In one embodiment, the subject is ahuman. In another embodiment, the subject is an adult, including a youngadult, mature adult, or elderly adult, or child, including a teenager.

The term “purified” as used herein preferably refers to Ibrutinib thatcontains less than about 1% impurities. In one embodiment, the Ibrutinibcontains less than about 0.5% impurities. In another embodiment, theIbrutinib contains less than about 0.1% impurities. In a furtherembodiment, the Ibrutinib is about 100% pure.

The terms intragranular and extragranular as used herein are known inthe art of formulations. An intragranular form of a formulationcomponent is added before granule formation. Similarly, an extragranularform of a formulation component is added to the granules of theformulation prior to compression. Simply stated, the extragranularportion breaks the composition into granules and the intragranularportion disintegrates the granules to release the Ibrutinib, a salt,prodrug, or metabolite thereof.

Abbreviations used herein include CCS (croscarmellose sodium), MCC(microcrystalline cellulose), SLS (sodium lauryl sulfate), HPMC(hydroxypropylmethylcellulose; hypromellose), DSC (differential scanningcalorimeter), BHT (butylated hydroxytoluene), BHA (butylatedhydroxyanisole), sodium methyl parahydroxybenzoate, sodium ethyl, CLL(chronic lymphocytic leukemia), and SLL (small lymphocytic lymphoma).

A. Ibrutinib Form

The compositions described herein contain Ibrutinib (Imbruvica) as theactive agent. Ibrutinib is described and may be prepared as set forth inU.S. Pat. Nos. 7,514,444; 8,003,309; 8,697,711; 8,735,403; 8,957,079;and 8,754,091, which are incorporated by reference. As known in the art,Ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the followingstructure. Ibrutinib has a melting point range of about 149° C. to about158° C., a partition coefficient of about 4 at a pH of about 7, adissociation constant of about 3.7, and a DSC melting point initiatingat about 156° C.

The Ibrutinib utilized herein may include other forms, includingmetabolites thereof, provided that the Ibrutinib form is stable andnon-toxic. The Ibrutinib form may also have some or the same activity asthe base Ibrutinib molecule. In one embodiment, an active metabolite ofIbrutinib is of the following structure.

The Ibrutinib form utilized herein may encompass tautomeric forms ofIbrutinib, prodrugs and salts. In one embodiment, the Ibrutinib saltsmay be derived from pharmaceutically or physiologically acceptableacids, bases, alkali metals and alkaline earth metals. Physiologicallyacceptable acids include those from inorganic and organic acids.Inorganic acids are known in the art and include, without limitation,hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, and phosphoricacids. Organic acids are also known in the art and include, withoutlimitation, lactic, formic, acetic, fumaric, citric, propionic, oxalic,succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic,anthranilic, salicylic, tartaric, malonic, mallic, phenylacetic,mandelic, embonic, methanesulfonic, ethanesulfonic, panthenoic,benzenesulfonic, toluenesulfonic, stearic, sulfanilic, alginic, andgalacturonic acids. Inorganic bases are known in the art and include,without limitation, aluminum, calcium, lithium, magnesium, potassium,sodium, and zinc sulfate or phosphates. Similarly, organic bases areknown in the art and include, without limitation,N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, and procaine. Alkali salts and alkalineearth metal salts can include, without limitation, sodium, potassium,calcium and magnesium salts in the form of esters, and carbamates.

Prodrugs of Ibrutinib are also contemplated and include, withoutlimitation, esters, carbamates, sulfates, ethers, oximes, carbonates,among others. The prodrug forms, which, when administered in such form,convert to the active moiety in vivo. See, Testa, “Prodrugs Revisited:The “Ad Hoc” Approach as a Complement to Ligand Design”, MedicinalResearch Reviews, 16(3):233-241, ed., John Wiley & Sons (1996), which isincorporated by reference.

A “metabolite” of Ibrutinib may also be utilized as described herein. Asknown in the art, a metabolite is a compound of Ibrutinib formed whenthe compound is metabolized as described in “The Pharmacological Basisof Therapeutics,” 9th Edition, McGraw-Hill (1996), which is incorporatedby reference.

B. Solid Formulations

Ibrutinib may be formulated in solid formulations for administration toa subject. The solid formulation is substantially dry, i.e., free fromliquid. In one embodiment, the solid formulation is about 90% or greaterdry.

In one embodiment, a pharmaceutical composition discussed hereincontains Ibrutinib, a salt, prodrug, or metabolite thereof,microcrystalline cellulose, croscarmellose sodium, sodium laurylsulfate, and magnesium stearate. As noted above, the Ibrutinib containedin this composition may be the base molecule, salt, prodrug, ormetabolite thereof.

The composition contains about 40 to about 45% by weight of Ibrutinib, asalt, prodrug, or metabolite thereof. In one embodiment, the compositioncontains about 41 to about 44% by weight of Ibrutinib, a salt, prodrug,or metabolite thereof. In a further embodiment, the composition containsabout 42 to about 43% by weight of Ibrutinib, a salt, prodrug, ormetabolite thereof. In another embodiment, the composition containsabout 42 or about 43% by weight of Ibrutinib, a salt, prodrug, ormetabolite thereof. In yet a further embodiment, the compositioncontains about 50 to about 140 mg of Ibrutinib, a salt, prodrug, ormetabolite thereof. In still another embodiment, the compositioncontains about 50 mg of Ibrutinib, a salt, prodrug, or metabolitethereof.

One or more suspending agent may be included in the liquid compositiondiscussed herein. In one embodiment, microcrystalline cellulose is alsoincluded in the compositions described herein. In further embodiments,the composition contains about 44 to about 47% by weight ofmicrocrystalline cellulose. In another embodiment, the compositioncontains about 45 to about 46% by weight of microcrystalline cellulose.

The compositions may also contain croscarmellose sodium. Thecroscarmellose sodium may be in an intragranular or extragranular form.In one embodiment, the composition contains about 6 to about 8% byweight of croscarmellose sodium. In another embodiment, the compositioncontains about 7% by weight of croscarmellose sodium. In a furtherembodiment, the composition contains about 3 to about 5% by weight ofintragranular croscarmellose sodium. In yet another embodiment, thecomposition contains about 4% by weight of intragranular croscarmellosesodium. In still a further embodiment, the composition contains about 2to about 4% by weight of extragranular croscarmellose sodium. In anotherembodiment, the composition contains about 3% by weight ofcroscarmellose sodium. In a further embodiment, the composition containsabout 13 mg of intragranular croscarmellose sodium and about 9.9 mg ofextragranular croscarmellose sodium. In a further embodiment, thecomposition contains about 4.6 mg of intragranular croscarmellose sodiumand about 3.5 mg of extragranular croscarmellose sodium.

Sodium lauryl sulfate may also be included in the compositions discussedherein. The sodium lauryl sulfate may be in intragranular and/orextragranular forms. In one embodiment, the composition contains about 1to about 5% by weight of sodium lauryl sulfate. In another embodiment,the composition contains about 2 to about 4.5% by weight of sodiumlauryl sulfate. In a further embodiment, the composition contains about3 to about 4% by weight of sodium lauryl sulfate. In still anotherembodiment, the composition contains about 2.5 to about 3% by weight ofintragranular sodium lauryl sulfate. In yet a further embodiment, thecomposition contains about 3% by weight of intragranular sodium laurylsulfate. In another embodiment, the composition contains about 1 toabout 2% by weight of extragranular sodium lauryl sulfate. In still afurther embodiment, the composition contains about 1.4% by weight ofextragranular sodium lauryl sulfate. In yet another embodiment, thecomposition contains about 9.4 mg of intragranular sodium lauryl sulfateand about 4.6 mg of extragranular sodium lauryl sulfate. In a furtherembodiment, the composition contains about 3.3 mg of intragranularsodium lauryl sulfate and about 1.6 mg of extragranular sodium laurylsulfate.

The compositions described herein may also contain magnesium stearate.The magnesium stearate may be in intragranular and/or extragranularforms. In one embodiment, the composition contains about 0.4 to about0.6% by weight of magnesium stearate. In another embodiment, thecomposition contains about 0.4 to about 0.5% by weight of magnesiumstearate. In another embodiment, the composition contains about 0.45 toabout 0.5% by weight of magnesium stearate.

In a further embodiment, the composition contains about 0.2 to about0.3% by weight of intragranular magnesium stearate. In still anotherembodiment, the composition contains about 0.2 to about 0.3% by weightof extragranular magnesium stearate. In yet a further embodiment, thecomposition contains about 0.8 mg of intragranular magnesium stearateand about 0.8 mg of extragranular magnesium stearate. In anotherembodiment, the composition contains about 0.3 mg of intragranularmagnesium stearate and about 0.3 mg of extragranular magnesium stearate.

In one embodiment, a pharmaceutical composition is described herein andincludes an intragranulation containing Ibrutinib, a salt, prodrug, ormetabolite thereof, microcrystalline cellulose, croscarmellose sodium,sodium lauryl sulfate, and magnesium stearate.

In another embodiment, the pharmaceutical composition includes anextragranulation containing croscarmellose sodium, sodium laurylsulfate, and magnesium stearate.

In a further embodiment, a pharmaceutical composition is provided andcontains (i) about 40 to about 45% by weight of Ibrutinib; (ii) about 44to about 47% by weight of microcrystalline cellulose; (iii) about 6 toabout 8% by weight of croscarmellose sodium; (iv) about 1 to about 5% byweight of sodium lauryl sulfate; and (v) about 0.2 to about 0.3% byweight of magnesium stearate.

In still another embodiment, a pharmaceutical composition is providedand contains (i) about 140 mg of Ibrutinib; (ii) about 151 mg ofmicrocrystalline cellulose; (iii) about 23 mg of croscarmellose sodium;(iv) about 14 mg of sodium lauryl sulfate; and (v) about 1.6 mg ofmagnesium stearate.

In yet a further embodiment, a pharmaceutical composition is providedand contains (i) about 50 mg of Ibrutinib; (ii) about 54 mg ofmicrocrystalline cellulose; (iii) about 8 mg of croscarmellose sodium;(iv) about 5 mg of sodium lauryl sulfate; and (v) about 0.6 mg ofmagnesium stearate.

In another embodiment, pharmaceutical compositions containing thecomponents of Table 1 are provided.

TABLE 1 Amount (mg) Amount (mg) 140 mg 50 mg Ingredient capsule capsuleIntragranular Ibrutinib, micronized (Lonza, Nansha) 140.00 50.00Microcrystalline Cellulose (Avicel PH 151.40 54.07 101) CroscarmelloseSodium (Ac-di-sol) 13.10 4.68 Sodium lauryl Sulfate (Kolliphor SLS 9.403.36 fine) Magnesium Stearate (Non-Bovine 0.80 0.29 #5712) ExtragranularCroscarmellose Sodium (Ac-di-sol) 9.90 3.54 Sodium lauryl Sulfate(Kolliphor SLS 4.60 1.64 fine) Magnesium Stearate (Non-Bovine 0.80 0.29#5712) Total fill weight 330.00 117.87 Hard Gelatin Capsule size 0 1 1

The solid compositions described herein contain particles of an optimalsize to permit dissolution of the composition, e.g., the particles areless than or equal to about 10 Ai. The sizes of the particles of thecomposition may be measured by passing the solid composition throughscreens of varying sizes. If the particles of the composition are largerthan the optimal size and if the same have not yet been encapsulated ina capsule or dissolved in one or more excipient, the same can be subjectto further milling and screening steps, among others, to reduce theparticle size. Ibrutinib may optionally be micronized under nitrogen andconventional micronizing techniques, for example with a Trost or jetmill, applied to non-micronized Ibrutinib. However, the compositionsdescribed herein are not limited to the method by which the Ibrutinib isproduced. Ibrutinib may have a median particle size of less than about10 μm, less than about 7 μm, or than about 5 μm. Specifically, 90% ofthe particles are less than or equal to about 10 μm and 50% are lessthan or equal to about 10 μm as determined by the Malvern method, whichis readily understood by one of skill in the art.

A variety of equipment may be utilized to perform the manufacturingprocesses of preparing the solid compositions and includes bags ofsmall, medium, and large sizes, screens of varying sizes, and blenders.The process may also include mixing, extruding, fusing, compactingand/or milling of the composition, typically using compactors and millsselected by those skilled in the art. The milling step may be performedon particles of varying sizes, i.e., large particles, powders, and finepowders to obtain a more uniform particle size. The milling may includeone or more separating, recycling, and screening steps to obtain thedesired particle sizes. In one embodiment, the compositions may beprepared by dry mixing Ibrutinib, based upon the total weight of thecomposition, with the other components of the composition. In anotherembodiment, the compositions described herein are prepared by wet mixingIbrutinib, based upon the total weight of the composition, with theother components of the composition. Drying may be performed usingdrying instruments selected by one of skill in the art. See, e.g.,Lachman, “The Theory and Practice of Industrial Pharmacy”, 3^(rd) ed.(1986), which is incorporated by reference.

In one embodiment, the solid compositions discussed herein are preparedby (a) blending microcrystalline cellulose, a first portion of sodiumlauryl sulfate, and a first portion of croscarmellose sodium; (b)blending the product of step (a) with a first portion of Ibrutinib; (c)blending the product of step (b) with a second portion of Ibrutinib; (d)blending the product of step (c) with a first portion of magnesiumstearate; (e) roller compacting the product of step (d); (f) milling theribbons produced in step (e); (g) blending the granules produced in step(f) with a second portion of sodium lauryl sulfate and croscarmellosesodium; and (h) blending the product of step (g) with a second portionof magnesium stearate. In another embodiment, the solid compositions areprepared as described in FIG. 1.

The solid compositions may then be formed into a suitable dosing unitfor delivery to a patient as determined by one skilled in the art.Suitable dosing units include oral dosing units. In one embodiment, thecomposition is added to a capsule. In a further embodiment, the capsuleis for pediatric administration. In yet another embodiment, the capsuleis for administration by an adult who is incapable of swallowing a soliddrug formulation. In another embodiment, the capsule is a HPMC(hypromellose) capsule. In yet a further embodiment, the capsule is agelatin capsule. In still another embodiment, the capsule is a hardgelatin capsule. In still another embodiment, the capsule is a standardor sprinkle capsule. In a further embodiment, the capsule is a Swedishorange capsule. In another embodiment, the capsule is a size 0 capsule.In yet another embodiment, the sprinkle capsule may be opened and thecontents added to a substance such as a food or drink which may beingested by the subject. The food may be a semi-solid or a solid,including soft food.

In another embodiment the capsules containing Ibrutinib are film-coated.Suitable film-coatings are known to those of skill in the art. Forexample, the film-coating may be a polymer such as HPMC, ethylcellulose, polyvinyl alcohol, or combinations thereof.

The solid compositions may also be added to a sachet. The term “sachet”as used herein refers to a bag or case which is capable of holding acomposition described herein. The size of the sachet depends on theamount of the composition to be added. In one embodiment, the sachet isa single dose sachet. In another embodiment, the sachet contains a bulkamount of the compositions described herein. In the latter case, thepatient, physician, or caretaker measures the appropriate dosage of thecompositions for administration. In a further embodiment, the sachet isa paper/aluminum/polyethylene laminate orpolyester/aluminum/polyethylene laminate, both of which may optionallybe located with a barrier coating such as ethylenevinyl acetate,polyvinyl acetate, polysiloxane, or melamine, among others. In anotherembodiment, the sachet may be opened and the contents added to asubstance such as a food or drink which may be ingested by the subject.The drink may include, without limitation, water, milk, or other commonbeverages.

The liquid formulation of solid composition (formulated in a liquid) maybe administered to a subject via a feeding tube. The feeding tube may betemporarily or permanently affixed to a patient using skill in the art.The patient may be conscious, semi-conscious, or asleep, depending onthe need as determined by the attending physician. Several types offeeding tubes are known in the art and may be selected by the attendingphysician.

C. Liquid Formulation

Ibrutinib may be also formulated in liquid formulations foradministration to a subject. Liquids include, without limitation,suspensions, syrups, and elixirs. These dosing units are readilyprepared using the methods described herein and those known to those ofskill in the art. When formulated as suspension, particle settling mayoccur, thereby requiring resuspending particles in the suspension usingskill in the art.

The liquid compositions described herein contain Ibrutinib, a salt,prodrug, or metabolite thereof, microcrystalline cellulose,carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acidmonohydrate, disodium hydrogen phosphate, sucralose, sodium methylparahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentratedhydrochloric acid, sodium hydroxide, and water.

Accordingly, the liquid composition contains about 30 to about 80 mg/mLof Ibrutinib, a salt, prodrug, or metabolite thereof. In someembodiments, the composition contains about 30 to about 50 mg/mL ofIbrutinib, a salt, prodrug, or metabolite thereof. In furtherembodiments, the composition contains about 40 mg/mL of Ibrutinib, asalt, prodrug, or metabolite thereof. In other embodiments, thecomposition contains about 60 to about 80 mg/mL to about 70 mg/mL ofIbrutinib, a salt, prodrug, or metabolite thereof. In yet furtherembodiments, the composition contains about 70 mg/mL of Ibrutinib, asalt, prodrug, or metabolite thereof.

One or more suspending agent may be included in the liquid compositiondiscussed herein. In one embodiment, microcrystalline cellulose andcarboxymethylcellulose sodium may also be included in the liquidcomposition. In some embodiments, the composition contains about 12 toabout 15 mg/mL of the suspending agent. In further embodiments, thecomposition contains about 13 to about 15 mg/mL of suspending agent. Inother embodiments, the composition contains about 12 to about 14 mg/mLof the suspending agent. In a further embodiment, the compositioncontains about 13 mg/mL of the suspending agent. In another embodiment,the composition contains about 14 mg/mL of the suspending agent.

The composition may also contain one or more of a wetting agent. In oneembodiment, the composition contains hydroxypropylmethylcellulose. Insome embodiments, the composition contains about 0.5 to about 3 mg/mL ofthe wetting agent. In other embodiments, the composition contains about2 to about 3 mg/mL of the wetting agent. In another embodiment, thecomposition contains about 2.5 mg/mL of the wetting agent. In furtherembodiments, the composition contains about 0.5 to about 1.5 mg/mL ofthe wetting agent. In yet other embodiments, the composition containsabout 1 mg/mL of the wetting agent.

One or more buffering agent may be included in the composition, solid orliquid. In one embodiment, the buffering agent is citric acidmonohydrate or disodium hydrogen phosphate. In another embodiment, thecomposition contains about 2.5 to about 3.5 mg/mL of a buffering agent.In some embodiments, the composition contains about 1 to about 1.5 mg/mLof a first buffering agent. In other embodiments, the compositioncontains about 0.5 to about 0.7 mg/mL of the buffering agent. In afurther embodiment, the composition contains about 1.5 mg/mL of a firstbuffering agent and about 1.5 mg/mL of a second buffering agent. Inother embodiments, the composition contains about 1.6 mg/mL of a firstbuffering agent and about 1.4 mg/mL of a second buffering agent. In yetanother embodiment, the composition contains about 1.5 mg/mL or 1.6mg/mL of citric acid monohydrate. In still a further embodiment, thecomposition contains about 1.4 mg/mL of disodium hydrogen phosphate.

Sweeteners may also be included in the compositions, solid or liquid,described herein. In one embodiment, the sweeter is sucralose. Inanother embodiment, the composition contains about 0.1 to about 1.5mg/mL of the sweetener. In other embodiments, the composition contains0.5 to about 1.5 mg/mL of the sweetener. In a further embodiment, thecomposition contains about 1 mg/mL of the sweetener. In anotherembodiment, the composition contains about 0.5 mg/mL of the sweetener.

One or more of a preservative may further be included in thecompositions, solid or liquid. The preservative desirably provides anoptimal microbiological activity in the liquid formulation. In oneembodiment, the composition retains the optimal activity of themethyl/ethyl parabens. In one embodiment, the preservative is sodiummethyl parahydroxybenzoate. In another embodiment, the preservative issodium ethyl parahydroxybenzoate. In a further embodiment, thecomposition contains about 1.5 to about 2.5 mg/mL of the preservative.In other embodiments, the composition contains about 1.5 to about 2mg/mL of the preservative. In a further embodiment, the compositioncontains about 0.5 to about 1.8 mg/mL of a first preservative. In yetanother embodiment, the composition contains about 1.0 to about 1.8mg/mL of a first preservative. In still a further embodiment, thecomposition contains about 1.25 to about 1.5 mg/mL of a secondpreservative. In another embodiment, the composition contains about 1.1mg/mL of a first preservative and about 0.6 mg/mL of a secondpreservative. In other embodiments, the composition contains about 1.4mg/mL of a first preservative and about 0.7 mg/mL of a secondpreservative. In yet a further embodiment, the composition containsabout 1 mg/mL of sodium methyl parahydroxybenzoate. In still anotherembodiment, the composition contains about 0.6 mg/mL of sodium ethylparahydroxybenzoate. In further embodiments, the composition containsabout 1.4 mg/mL of sodium methyl parahydroxybenzoate. In still anotherembodiment, the composition contains about 0.7 mg/mL of sodium ethylparahydroxybenzoate.

If the pH of the solution requires adjustment, a pH adjustor may beincluded in the composition. One of skill in the art would be ableselect suitable pH adjustor to ensure a safe, stable andsubject-compatible composition. In one embodiment, the pH of thecomposition is adjusted to about 6. In another embodiment, the pHadjustor is an acid or base. In a further embodiment, the pH adjustor ishydrochloric acid. In still another embodiment, the pH adjustor isconcentrated hydrochloric acid. In yet a further embodiment the pHadjustor is sodium hydroxide.

Finally, a sufficient amount of a diluent, such as water, may beincluded in the composition to ensure a volume of about 1 mL. In oneembodiment, the diluent is purified water. Compositions containinglesser amounts of Ibrutinib can prepared as described herein by dilutingcompositions containing greater amounts of Ibrutinib using the diluent.

In one embodiment, a pharmaceutical composition is provided and contains(i) about 70 mg/mL of Ibrutinib; (ii) about 13 mg/mL of microcrystallinecellulose and carboxymethylcellulose sodium; (iii) about 2.5 mg/mL ofhydroxypropylmethylcellulose; (iv) about 1.5 mg/mL of citric acidmonohydrate; (v) about 1.4 mg/mL of disodium hydrogen phosphate; (vi)about 1 mg/mL of sucralose; (vii) about 1 mg/mL of sodium methylparahydroxybenzoate; and (viii) about 0.6 mg/mL of sodium ethylparahydroxybenzoate.

In another embodiment, a pharmaceutical composition is provided andcontains the components of Table 2.

TABLE 2 Concentration Component (mg/mL) Ibrutinib micronized 70 MCC andCMC 13 HPMC 2.5 Citric acid monohydrate 1.513 Disodium hydrogenphosphate 1.38 Sucralose 1 Sodium methyl parahydroxybenzoate 1.145Sodium ethyl parahydroxybenzoate 0.575

In other embodiments, a pharmaceutical composition is provided andcontains (i) about 40 mg/mL of Ibrutinib; (ii) about 14 mg/mL ofmicrocrystalline cellulose and carboxymethylcellulose sodium; (iii)about 1 mg/mL of hydroxypropylmethylcellulose; (iv) about 1.6 mg/mL ofcitric acid monohydrate; (v) about 1.4 mg/mL of disodium hydrogenphosphate; (vi) about 0.5 mg/mL of sucralose; (vii) about 1.4 mg/mL ofsodium methyl parahydroxybenzoate; and (viii) about 0.7 mg/mL of sodiumethyl parahydroxybenzoate.

In further embodiments, a pharmaceutical composition is provided andcontains the components of Table 3.

TABLE 3 Concentration Component (mg/mL) Ibrutinib micronized 40 MCC andCMC 14 HPMC 1 Citric acid monohydrate 1.602 Disodium hydrogen phosphate1.38 Sucralose 0.5 Sodium methyl parahydroxybenzoate 1.3582 Sodium ethylparahydroxybenzoate 0.6773

The liquid compositions may be prepared by (a) mixing water,microcrystalline cellulose croscarmellose sodium; (b) mixing water withhydroxypropylmethylcellulose; (c) mixing the product of step (b) withIbrutinib; (d) mixing the product of steps (a) and (c); (e) mixing theproduct of step (d) with sucralose; (f) mixing the product of step (e)with sodium methyl parahydroxybenzoate and sodium ethylparahydroxybenzoate; (g) mixing the product of step (f) with monohydratecitric acid; and (h) mixing the product of step (g) with anhydrousdisodium hydrogen phosphate. The process my further include (i)adjusting the pH of the product of step (h) to a pH of about 6. In oneembodiment, step (i) is performed using hydrochloric acid or sodiumhydroxide. The process may also include adding water to the product ofstep (h) or (i). It is also envisioned that the product of step (a) maybe homogenized using skill known in the art.

Liquid formulations may then be stored as a bulk unit or distributedinto separate, smaller vials for storage or purchasing by the customer.One of skill in the art would readily be able to select suitable vialsfor use herein. In one embodiment, the liquid composition is added to avial. In a further embodiment, the vial is glass. In another embodiment,the vial is clear or amber. In a further embodiment, the vial may besealed. In yet another embodiment, the vial is sealed with a rubberstopper. In a further embodiment, the vial is sealed with a Tefloncoated rubber stopper. The stopper optionally contains a removable,i.e., tearable, aluminum cap. In still another embodiment, the vial is a10 mL/20 mm vial. In yet a further embodiment, the vial is a drinkingvial.

Additionally, the drug product will be administered as mono dose to eachsubject after a suitable sample shaking to resuspend particles beforeadministration. Furthermore, after drug product administration, vialwill be rinsed with an adequate amount of water and the entire contentsof the vial will be administered to subject. For reasons mentionedabove, even if settling happens, it is not expected to have an effect onthe delivered dose.

D. Additional Components

Other components can be added to the compositions described herein asdetermined by one of skill in the art. The additional components may beinert and do not interfere with the function of the required componentsof the compositions. The compositions may, therefore, include otheradjuvants, syrups, elixirs, diluents, binders, lubricants, surfactants,granulating agents, disintegrating agents, emollients, metal chelators,pH adjustors, coloring preservatives, antioxidants, agents, surfactants,fillers, disintegrants, or combinations thereof.

Preservatives may include ascorbic acid, BHT and BHA, sodium methylparahydroxybenzoate, sodium ethyl parahydroxybenzoate, or combinationsthereof.

Sweeteners such as natural or artificial sweeteners, or a combinationthereof, may be included in the compositions described herein. In oneembodiment, the natural sweetener is sucrose including raw sugar,granulated sugar, brown sugar, confectioner's sugar, and turbinadosugar, fructose, honey, fruit sugar, high fructose corn syrup, cornsyrup, sugar alcohols such as mannitol, sorbitol, xylitol, erythritol,hydrogenated starch hydrolysate, lactitol, or maltitol, osmalt,dextrose, invert sugar, agave nectar, glucose, lactose, maltose, maplesugar, date sugar, molasses, stevia extract, tagatose, trehalose, or anycombinations thereof. Another embodiment, the artificial sweetener issucralose, aspartame, saccharine, neotame, advantame, or acesulfamepotassium. In still a further embodiment, sugar may be included in thecompositions.

Binders may include, without limitation, cellulose, methylcellulose,hydroxymethylcellulose, carboxymethylcellulose calcium,carboxymethylcellulose sodium, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,polypropylpyrrolidone, polyvinylpyrrolidone (povidone, PVP), gelatin,gum arabic and acacia, polyethylene glycols, starch, sugars such assucrose, kaolin, dextrose, and lactose, cholesterol, tragacanth, stearicacid, gelatin, casein, lecithin (phosphatides), cetostearyl alcohol,cetyl alcohol, cetyl esters wax, dextrates, dextrin, glycerylmonooleate, glyceryl monostearate, glyceryl palmitostearate,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives,polyoxyethylene stearates, polyvinyl alcohol, and gelatin, among others.

Lubricants may include anhydrous silicic acid, talc, stearic acid,sodium lauryl sulfate, magnesium stearate and sodium stearyl fumarate,among others.

Granulating agents may include, without limitation, silicon dioxide,starch, calcium carbonate, pectin, crospovidone, and polyplasdone.

Disintegrating agents or disintegrants may include, without limitation,starch, carboxymethylcellulose, substituted hydroxypropylcellulose,sodium bicarbonate, calcium phosphate, calcium citrate, sodium starchglycolate, pregelatinized starch or crospovidone.

Emollients may include, without limitation, stearyl alcohol, mink oil,cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol,olive oil, petroleum jelly, palmitic acid, oleic acid, and myristylmyristate.

Surfactants may include, without limitation, polysorbates, sorbitanesters, poloxamer, or sodium lauryl sulfate.

Metal chelators may include, without limitation, physiologicallyacceptable chelating agents including edetic acid, malic acid, orfumaric acid.

The compositions described herein, in dry or liquid form, have a pH ofabout 5.5 to about 6.5. pH adjusters may be utilized to adjust the pH ofa solution containing Ibrutinib to about 6. pH adjustors may include,without limitation, citric acid, ascorbic acid, fumaric acid, malicacid, hydrochloric acid, sodium hydroxide, salts thereof, orcombinations thereof.

E. Stability of the Compositions

The Ibrutinib compositions as described herein, whether in solid orliquid form, are stable under neutral conditions, i.e., a pH of about 6to about 8. The compositions are also stable under light irradiation. Inone embodiment, the compositions are stable over a period of about 1month for samples stored at varying temperatures and humidities. Theterm stable as used herein refers to the compositions described hereinwhich degrade less than about 3%. In one embodiment, the compositionsare stable at about 20° C./50% relative humidity to about 45° C./75%relative humidity. In another embodiment, the compositions describedherein degrade less than about 3% over a period of greater than 1 monthat temperatures at or greater than about 25° C. and a relative humidityat or greater than about 60%.

The solid compositions are also stable for at least about 6 hours whencombined with an agent that is semi-solid or liquid. In one embodiment,the solid compositions may be suspended in a liquid or semi-solid andre-dispersed after 6 hours. In another embodiment, the solidcompositions suspended in a liquid or semi-solid are stable for up toabout 6 hours.

Stability may be monitored by a number of methods known in the art. Inone embodiment, the capsules and liquids may be observed to detect anyphysical aspect or color change. In one embodiment, a capsule colorchange or deformation of the capsule may indicate degradation ordeterioration of capsule and thus affect safety or efficacy.

The compositions described herein may be stored at reduced, room, orelected temperatures. In one embodiment, the compositions are stored attemperatures of about 0 to about 10° C. In another embodiment, thecompositions are stored at temperatures of about 2 to about 8° C. Thecompositions may be stored in the absence of water, air, and moisture.However, storage at room temperature, among other atmosphericconditions, does not affect the overall stability of the compositions.

F. Methods of Using the Compositions

Also provided are method of delivering Ibrutinib to a patient, where themethod includes administering a composition described herein to apatient. The compositions are thereby useful in treating or preventingconditions. In some embodiments, the conditions are those recited inU.S. Pat. Nos. 8,497,277; 8,476,284; 8,703,780; and 8,754,090, which areincorporated by reference herein.

The compositions are useful in therapeutically treating a subject havingone or more of any of the conditions noted herein. The compositions mayalso be prophylactically useful, i.e., the compositions may beadministered to a patient susceptible to or otherwise at risk ofdeveloping a malignancy. The compositions may further be used inmaintenance therapy, i.e., administered to a patient who is inremission.

In certain embodiments, the methods include treating one or moreautoimmune disease. In one embodiment, the autoimmune disorder isinflammatory bowel disease, arthritis, lupus, rheumatoid arthritis,psoriatic arthritis, osteoarthritis, Still's disease, juvenilearthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Graves' disease, Sjogren's syndrome, multiple sclerosis,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylitisis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, coeliac disease, Goodpasture's syndrome, idiopathicthrombocytopenic purpura, optic neuritis, scleroderma, primary biliarycirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis,warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis,alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, orvulvodynia.

In other embodiment, the methods include treating one or moreheteroimmune disorder. In one embodiment, the heteroimmune disorder isgraft versus host disease, transplantation, transfusion, anaphylaxis,allergy, type I hypersensitivity, allergic conjunctivitis, allergicrhinitis, or atopic dermatitis.

In certain embodiments, the methods include treating one or moreinflammatory disease. In one embodiment, the inflammatory disease isarthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In still other embodiments, the methods include treating one or morecancer. In one embodiment, the cancer is a B-cell proliferativedisorder. In still another embodiment, the cancer is a hematologicalmalignancy. In a further embodiment, the cancer is B-cell prolymphocyticleukemia, leukemia, lymphoma, lymphoproliferative disorder,lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, myeloiddisorder, plasma cell myeloma, plasmacytoma, mediastinal large B celllymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, lymphomatoid granulomatosis, non-Hodgkin's CLL, SLL, high riskCLL, non-CLL/SLL lymphoma, follicular lymphoma, diffuse large B-celllymphoma, mantle cell lymphoma, multiple myeloma, marginal zonelymphoma, non-Burkitt high grade B cell lymphoma, extranodal marginalzone B cell lymphoma, acute or chronic myelogenous leukemia,myelodysplastic syndrome, lymphoblastic leukemia, relapsed or refractorydiffuse large B-cell lymphoma, relapsed or refractory mantle celllymphoma, relapsed or refractory follicular lymphoma, relapsed orrefractory CLL, relapsed or refractory SLL, relapsed or refractorymultiple myeloma, Burkitt's lymphoma, cutaneous B-cell lymphoma,cutaneous marginal zone lymphoma, diffuse mixed small and large celllymphoma, diffuse small cleaved cell, extranodal follicular smallcleaved cell, follicular mixed small cleaved and large cell, follicularlarge cell, intravascular lymphomatosis, large cell immunoblasticlymphoma, large cell lymphoma, mucosa associated lymphoid tissueLymphoma, immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma,primary mediastinal B-cell lymphoma, hairy cell leukemia, and primarycentral nervous system lymphoma. In another embodiment, the B-cellproliferative disorder is non-Hodgkin lymphoma, Waldenstrommacroglobulinemia, plasma cell myeloma, or chronic lymphocytic leukemia.In a further embodiment, the B-cell proliferative disorder is diffuselarge B cell lymphoma, follicular lymphoma, mantle cell lymphoma andBurkitt lymphoma. In still another embodiment, the cancer is leukemia.In yet another embodiment, the cancer is a lymphoma.

In yet other embodiments, the methods include treating a thromboembolicdisorder. In one embodiment, the thromboembolic disorder is myocardialinfarct, angina pectoris, reocclusion after angioplasty, restenosisafter angioplasty, reocclusion after aortocoronary bypass, restenosisafter aortocoronary bypass, stroke, transitory ischemia, a peripheralarterial occlusive disorder, pulmonary embolism, or deep venousthrombosis.

The dosage requirements of Ibrutinib may vary based on the severity ofthe symptoms presented and the particular subject being treated.Treatment may be initiated with small dosages less than the optimum doseof Ibrutinib. Thereafter the dosage may be increased until the optimumeffect under the circumstances is reached. Precise dosages will bedetermined by the administering physician based on experience with theindividual subject treated. In one embodiment, the composition isadministered at a concentration that will afford effective resultswithout causing any unacceptable harmful or deleterious side effects.

The term “effective amount,” as used herein, refers to a sufficientamount of an agent or a compound being administered which will relieveone or more symptom of a B-cell proliferative disorder. The result maybe reduction and/or alleviation of the signs, symptoms, or causes of thedisorder. In certain embodiments, the effective amount achieves thedesired pharmacologic effect or therapeutic improvement without undueadverse side effects.

An effective amount of Ibrutinib can vary depending on the components ofthe composition, mode of delivery, severity of the condition beingtreated, the patient's age and weight, and any other active ingredientsused in the composition. The dosing regimen can also be adjusted toprovide the optimal therapeutic response. Several divided doses may bedelivered daily, e.g., in divided doses 2 to 4 times a day, or a singledose can be delivered. The dose can however be proportionally reduced orincreased as indicated by the exigencies of the therapeutic situation.In one embodiment, the delivery is on a daily, weekly, or monthly basis.In another embodiment, the delivery is on a daily delivery. Thecomposition may be administered daily. In some embodiments, thecomposition may be administered every other day. In some embodiments,the composition may be administered once or more times per day. In someembodiments, the composition may be administered two or more times perday. In some embodiments, the composition may be administered three ormore times per day.

The dosages may also be lowered or raised based on the periodicdelivery. The attending physician also has the flexibility to continuethe same administration for a period of time or may decide to alter theadministration schedule. This may be as a result of improved conditions,adverse, but not fatal, reactions to the composition, or the like. Ifadministration is halted, re-administration may be continued if thepatient stabilizes or improvement of the condition has materialized.Accordingly, the dosage, frequency of administration, or combinationthereof may be reduced or increased as needed.

The amount of Ibrutinib administered may vary depending upon severity ofthe disease, weight of the subject, age of the subject, among others. Inone embodiment, an effective amount is about 0.1 to about 5000 mg/day.In one embodiment, an effective amount of Ibrutinib is about 1 to about1500 mg/day. In another embodiment, the effective amount of Ibrutinib isabout 20 to about 450 mg/day. In a further embodiment, the effectiveamount of Ibrutinib is about 20 to about 420 mg/day. In yet anotherembodiment, the effective amount of Ibrutinib is about 30 to about 300mg/day. In still a further embodiment, the effective amount of Ibrutinibis about 50 to about 200 mg/day. In another embodiment, the effectiveamount of Ibrutinib is about 70 to about 140 mg/day.

The desired dose may conveniently be presented in a single dose or asdivided doses administered simultaneously (or over a short period oftime) or at appropriate intervals, for example as two, three, four ormore sub-doses per day.

The compositions may be delivered to the subject by any suitable routeas directed by the attending physician. In one embodiment, thecompositions are delivered orally.

The compositions may be co-administered with one or more of a secondagent. The second agent may be administered prior to, concurrently with,or subsequent to the compositions discussed herein. In some embodiments,the second agent comprises a chemotherapeutic agent, steroid,immunotherapeutic agent, among others. In another embodiment, the secondagent is one or more of actinomycines, alkylating agents, alitretinoin,altretamine, amzacrine, anagrelide, angiogenesis inhibitors, antibody,anti-androgens, anti-estrogens, anti metabolites, anthracyclines,arsenic trioxide, asparaginase, B cell receptor pathway inhibitor (CD79Ainhibitor, CD79B inhibitor, CD 19 inhibitor, Lyn inhibitor, Sykinhibitor, PI3K inhibitor, Blnk inhibitor, PLCγ inhibitor, PKCPinhibitor), basiliximab, bexarotene, bortezomib, calcineurin inhibitors,canakinumab, celecoxib, ceradenovec, colchicine derivatives, cytotoxicantibiotics, daclizumab, denileukin diftitox, DNA damaging agent,epoxides, estramustine, estrogens, ethylene imines, folic acidanalogues, gonadotropin releasing interferons, growth factors, HDACinhibitor, hedgehog inhibitor, Hsp90 inhibitor, histone deacetylaseinhibitor, hormones, hormone analogs, hormone antagonists,hydroxycarbamide, IAP inhibitor, ibritumomab immunostimulants,immunosuppressants, interleukin inhibitors, interleukins, irinotecan,Jak1/2 inhibitor, lonidamine, masoprocol, mepolizumab, miltefosein,mitoguazone, mitotane, monoclonal antibodies, mTOR inhibitor,methylhydrazines, nitrogen mustards, nitrosoureas, PI3K inhibitor,oblimersen, PARP inhibitor, pegaspargase, pentostatin, PKC inhibitor,plant alkaloids, platinum compounds (carboplatin, cisplatin,oxaliplatin, or satraplatin), podophyllotoxin derivatives, progestogens,proteasome inhibitor, protein kinase inhibitor, protease inhibitor,purine analogs, pyrimidine analogs, radioimmunotherapeutic, sensitizers,romidepsin, sitimagene tiazofurine, topotecan, tretinoin, tumor necrosisfactors, TNF-α Inhibitors, tocilizumab, telomerase inhibitor, tiuxetan,tositumomabtriazenes, ustekinumab, vinca alkaloids, or vorinostat. In afurther embodiment, the second agent includes, Adriamycin, dactinomycin,bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; alemtuzumab,altretamine; ambomycin; ametantrone acetate; aminoglutethimide;amsacrine; anastrozole; anthramycin; asparaginase; asperlin;azacitidine; azetepa; azotomycin; batimastat; bendamustine, bevacizumab;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; cetuximab;chlorambucil; cirolemycin; cladribine; crisnatol mesylate; Crizotinib;cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride;decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene;droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate;eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; erbulozole; esorubicinhydrochloride; estramustine; estramustine phosphate sodium; etanidazole;etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride;fazarabine; fenretinide; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; 5-fluorouracil; fosquidone; fostriecinsodium; gemcitabine; gemcitabine hydrochloride; gemtuzamab; hydroxyurea;idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II,interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3;interferon β-1 a; interferon γ-1 b; iproplatin; irinotecanhydrochloride; lanreotide acetate; letrozole; leuprolide acetate;liarozole hydrochloride; lometrexol sodium; lomustine; losoxantronehydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride;megestrol acetate; melengestrol acetate; melphalan; menogaril;mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; Nexavar®; nocodazoie; nogalamycin; ofatumumab; ormaplatin;oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycinsulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;prednimustine; procarbazine hydrochloride; puromycin; puromycinhydrochloride; pyrazofurin; riboprine; rituaximab; rogletimide,safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; Sprycel®; streptonigrin; streptozocin; sulofenur; Sutent®;talisomycin; Tarceva®; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; temozolomide; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; Tykerb®; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; wortmannin; zeniplatin; zinostatin;zorubicin hydrochloride.

G. Kits Containing the Compositions

Also provided are kits or packages containing Ibrutinib and an optionalcarrier suitable for administration to a mammalian subject as discussedabove. In one embodiment, the capsules may be packaged in bottles,blister packs, pill boxes, or the like. In another embodiment, theliquid formulation may be packaged in a bottle optionally coated with apiercable cap, ampule, drop counter, or in a saline bag.

The kits or packages containing the compositions described herein aredesigned for use in the methods described herein. The kit can optionallyfurther contain instructions for administering composition, a carriersuitable for administration of the composition, one or more instrumentsincluding, without limitation, syringe, pipette, forceps, measuringspoon, or the like. Other components for inclusion in the kits would beclear to those skilled in the art, taking into consideration the desiredindication and mode of delivery.

The following Examples are provided to illustrate some of the conceptsdescribed within this disclosure. While each Example is considered toprovide specific individual embodiments of composition, methods ofpreparation and use, none of the Examples should be considered to limitthe more general embodiments described herein.

In the following examples, efforts have been made to ensure accuracywith respect to numbers used (e.g. amounts, temperature, etc.) but someexperimental error and deviation should be accounted for. Unlessindicated otherwise, temperature is in degrees C., pressure is at ornear atmospheric.

EXAMPLES Example 1: Solid Compositions Containing Ibrutinib

Solid compositions containing Ibrutinib were prepared for inclusion in acapsule as described in the following.

A. 140 mg Capsule

In this process, an intragranular blend was prepared by mixing MCC(151.49 mg; Avicel PH 101), SLS (9.40 mg; Kolliphor; fine), and CCS(13.10 mg; Ac-di-sol) in a vessel. This was then mixed with Ibrutinib(70 mg; micronized, Lonza, Nansha). The remaining Ibrutinib (70 mg) wasthen added and the composition mixed. Magnesium stearate (0.8 mg;Non-Bovine #5712) was then added to this mixture and the same blended toprovide a pre-roller compaction blend. The pre-roller compaction blendwas then roller compacted to form ribbons. The ribbons were then milledto provide a composition containing granules.

The granules were then blended with a second portion of SLS (4.6 mg;Kolliphor; fine) and CCS (9.9 mg; Ac-di-sol). To this blend was thenadded a second portion of magnesium stearate (0.8 mg; Non-Bovine #5712)to provide a lubricated blend. This lubricated blend was then added to asize 0 Swedish orange hard gelatin capsule.

B. 50 mg Ibrutinib Capsule

In this process, an intragranular blend was prepared by mixing MCC(54.07 mg; Avicel PH 101), SLS (3.36 mg; Kolliphor; fine), and CCS (4.68mg; Ac-di-sol). This was then mixed with Ibrutinib (25 mg; micronized,Lonza, Nansha). The remaining Ibrutinib (25 mg) was then added and thecomposition mixed. Magnesium stearate (0.29 mg; Non-Bovine #5712) wasthen added to this mixture and the same blended to provide a pre-rollercompaction blend. The pre-roller compaction blend was then rollercompacted to form ribbons. The ribbons were then milled to provide acomposition containing granules.

The granules were then blended with a second portion of SLS (1.64 mg;Kolliphor; fine) and CCS (3.54 mg; Ac-di-sol). To this blend was thenadded magnesium stearate (0.29 mg; Non-Bovine #5712) to provide alubricated blend. This lubricated blend (117.87 mg) was then added,independently, to a size 0 Swedish orange hard gelatin capsule and aSwedish orange sprinkle capsule.

Example 2: Liquid Suspension Composition Containing Ibrutinib

(i) 70 mg/mL Ibrutinib Liquid Suspension

A liquid composition containing 70 mg/mL of Ibrutinib was prepared.Specifically, water (300 mL) was mixed with a composition MCC of CCS(Avicel RC591; 6.5 g) for 30 minutes. This dispersion was thenhomogenized for 30 seconds using a SILVERSON® homogenizer L2R at themaximal speed (7500 rpm). HPMC (2910 5 mPas; 1.25 g) was mixed withwater (120 mL) until homogeneous using a magnetic stirrer. MicronizedIbrutinib (35 g, Lonza Clinical) was then added to the HPMC solution andmixed for 120 minutes. The MCC/CCS dispersion was then mixed with theIbrutinib mixture. Sucralose (0.5 g), sodium methyl parahydroxybenzoate(0.5725 g), and sodium ethyl parahydroxybenzoate (0.2875 g) were addedto the mixture. After about 10 minutes stirring, citric acid monohydrate(0.7565 g), and disodium hydrogen phosphate anhydrous parenteral (0.69g) were then added to this mixture. The mixture was stirred for about 10minutes until the content solubilized. The pH of the mixture wasmeasured and found to be 5.99, thereby eliminating the need to adjustthe pH. The mixture was then diluted with purified water until a finalweight of 510.5 g. The mixture was again measured and found to be about6.

The concentration for each component in the final liquid composition isprovided in Table 2.

(ii) 40 mg/mL Ibrutinib Liquid Suspension

A liquid composition containing 40 mg/mL of Ibrutinib was prepared.Specifically, water (300 mL) was mixed with a composition MCC of CCS(Avicel RC591; 7 g) for 30 minutes. This dispersion was then homogenizedfor 30 seconds using a SILVERSON® homogenizer L2R at the maximal speed(7500 rpm). HPMC (2910 5 mPas; 0.5 g) was mixed with water (120 mL)until homogeneous using a magnetic stirrer. Micronized Ibrutinib (20 g,Lonza Clinical) was then added to the HPMC solution and mixed for 120minutes. The MCC/CCS dispersion was then mixed with the Ibrutinibmixture. Sucralose (0.25 g), sodium methyl parahydroxybenzoate (0.6791g) and sodium ethyl parahydroxybenzoate (0.3387 g) were added to themixture. After about 10 minutes stirring, citric acid monohydrate (0.801g), and disodium hydrogen phosphate anhydrous parenteral (0.69 g) werethen added to this mixture. The mixture was stirred for about 10 minutesuntil the contents solubilized. The pH of the mixture was measured andfound to be about 5.99, thereby eliminating the need to adjust the pH.The mixture was then diluted with purified water until final weight of507 g. This mixture was then homogenized. The pH was again measured andfound to be about 6.

The concentration for each component in the final liquid composition isprovided in Table 3.

Example 3: Large Scale Preparation of a Suspension Containing IbrutinibPreparation of 4 L Batch

Purified water (480 g) was added to a vessel and warmed to about 83° C.at a stirring rate of about 400 rpm for about 60 minutes. HPMC (10.002g) was slowly added to the vessel and the mixture stirred at a rate ofabout 7600 rpm for about 4 minutes until the mixture was homogenized. Tothis vessel was added purified water (480 g) and then mixture wasstirred for about 5 minutes at a rate of about 500 rpm at roomtemperature until the mixture was solubilized. Ibrutinib (278.6 g) wasadded to the mixture and it was stirred at 600 rpm for about 2 h untilit was homogenous. The mixture was monitored using a microscope foragglomerates.

Purified water (2400 g) was then added to a second vessel. At a rate ofabout 500 rpm, MCC (51.74 g; Avicel) was added to the second vessel overa period of 3 minutes, followed by stirring at a rate of about 400 rpmfor about 60 minutes. This mixture was then homogenized using a stirringspeed of about 7600 tr/min over a period of about 4 minutes. The mixturewas monitored using a microscope for agglomerates.

The mixture in the first vessel was then added to the mixture in thesecond vessel and the combined contents stirred for about 5 minutes at aspeed of about 500 rpm. The first vessel was then rinsed using purifiedwater (200 ml) and the same added to the second vessel. Under moderatestirring conditions, sucralose (4.0038 g), sodium methylparahydroxybenzoate (4.5838 g), and sodium ethyl parahydroxybenzoate(2.300 g) were sequentially added to the second vessel and the mixturestirred for about 11 minutes until the solids solubilized. Citric acidmonohydrate (6.052 g) was then added to the second vessel and themixture stirred for about 10 minutes. Anhydrous disodium hydrogenphosphate (5.521 g) was then added and the mixture was stirred for about10 minutes until the contents solubilized. The pH of the solution wasmeasured and found to be about 5.94, thereby eliminating the need toadjust the pH.

The mixture was then diluted using purified water (4064 g) until a finalweight of 4084 g. This mixture was then homogenized. The pH was againmeasured and found to be about 5.98. Aliquots (8 ml) of the mixture werethen removed under constant stirring at a speed of about 500 to about1300 rpm over a period of about 75 minutes. Each aliquot was added to aan amber, glass vial (10 ml), a Flurotec coated rubber injection stopper(20 mm) then inserted into the vial, and the stopper affixed with analuminum tear-off cap (20 mm). See, FIG. 3.

Example 4: Stability Studies of Ibrutinib Formulations

The stability of the solid composition described herein was evaluated in3 liquids. Specifically, the contents of 4 sprinkle capsules describedherein (each containing 140 mg of solid composition) were dissolved inwater (100 mL), milk (100 mL), and orange juice (100 mL) at roomtemperature. After about 6 hours, the colors of the milk and orangejuice solutions remained unchanged, while the water solution turnedmilky white.

It was found using liquid chromatography that the three Ibrutinibformulations were stable. Specifically, most of the Ibrutinib activeagent with minor amounts of impurities was recovered from theseformulations after sitting for 6 hours.

Example 5: Feeding Tube Studies Using Ibrutinib Formulations

Feasibility studies were conducted on feeding tubes using a compositiondescribed herein. Specifically, two formulations were prepared, eachformulation containing water (20 mL) and the contents of 4 sprinklecapsules described herein (total of 560 mg of active equivalentgranules). Upon passing the formulations through size 2.2 mm and 2.7 mmID feeding tubes, it was observed that the formulations (containing thewater and composition) passed through the tubes by gravity force andwithout clogging.

It was also found that the tubes could be re-used before theintroduction of another formulation. Specifically, air was blown throughthe tubes by applying a small amount of pressure using a syringe.Additional formulations could then be passed through the tubes withoutany interruption. It is to be understood that while the invention hasbeen described in conjunction with the preferred specific embodimentsthereof, that the foregoing description and the examples that follow areintended to illustrate and not limit the scope of the invention. It willbe understood by those skilled in the art that various changes may bemade and equivalents may be substituted without departing from the scopeof the invention, and further that other aspects, advantages andmodifications will be apparent to those skilled in the art to which theinvention pertains. In addition to the embodiments described herein, thepresent invention contemplates and claims those inventions resultingfrom the combination of features of the invention cited herein and thoseof the cited prior art references which complement the features of thepresent invention. Similarly, it will be appreciated that any describedmaterial, feature, or article may be used in combination with any othermaterial, feature, or article, and such combinations are consideredwithin the scope of this invention.

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, each in its entirety, for all purposes.

What is claimed is:
 1. A pharmaceutical composition comprisingIbrutinib, a salt, prodrug, or metabolite thereof, microcrystallinecellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose,citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodiummethyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate,concentrated hydrochloric acid, sodium hydroxide, and water.
 2. Thepharmaceutical composition of claim 1, comprising about 30 to about 80mg/mL of Ibrutinib.
 3. The pharmaceutical composition of claim 1,comprising about 30 to about 50 mg/mL of Ibrutinib.
 4. Thepharmaceutical composition of claim 1, comprising about 60 to about 80mg/mL of Ibrutinib.
 5. The pharmaceutical composition of claim 1,comprising about 12 to about 15 mg/mL of microcrystalline cellulose andcarboxymethylcellulose sodium.
 6. The pharmaceutical composition ofclaim 1, comprising about 13 to about 15 mg/mL of microcrystallinecellulose and carboxymethylcellulose sodium.
 7. The pharmaceuticalcomposition of claim 1, comprising about 12 to about 14 mg/mL ofmicrocrystalline cellulose and carboxymethylcellulose sodium.
 8. Thepharmaceutical composition of claim 1, comprising about 0.5 to about 3mg/mL of hydroxypropylmethylcellulose.
 9. The pharmaceutical compositionof claim 1, comprising about 2 to about 3 mg/mL ofhydroxypropylmethylcellulose.
 10. The pharmaceutical composition ofclaim 1, comprising about 0.5 to about 1.5 mg/mL ofhydroxypropylmethylcellulose.
 11. The pharmaceutical composition ofclaim 1, comprising about 1.4 to about 1.7 mg/mL of citric acidmonohydrate.
 12. The pharmaceutical composition of claim 1, comprisingabout 1.4 mg/mL of disodium hydrogen phosphate.
 13. The pharmaceuticalcomposition of claim 1, comprising about 0.5 to about 1.5 mg/mL ofsucralose.
 14. The pharmaceutical composition of claim 1, comprisingabout 1 to about 1.5 mg/mL of sodium methyl parahydroxybenzoate.
 15. Thepharmaceutical composition of claim 1, comprising about 0.5 to about 0.7mg/mL of sodium ethyl parahydroxybenzoate.
 16. The pharmaceuticalcomposition of claim 1, comprising a sufficient amount of concentratedhydrochloric acid to sustain a pH of about
 6. 17. The pharmaceuticalcomposition of claim 1, comprising a sufficient amount of sodiumhydroxide to sustain a pH of about
 6. 18. The pharmaceutical compositionof claim 1, comprising a sufficient amount of water to ensure a totalvolume of 1 mL.
 19. The pharmaceutical composition of claim 1, which isa liquid suspension.
 20. The pharmaceutical composition of claim 1,comprising: (i) about 70 mg/mL of Ibrutinib; (ii) about 13 mg/mL ofmicrocrystalline cellulose and carboxymethylcellulose sodium; (iii)about 2.5 mg/mL of hydroxypropylmethylcellulose; (iv) about 1.5 mg/mL ofcitric acid monohydrate; (v) about 1.4 mg/mL of disodium hydrogenphosphate; (vi) about 1 mg/mL of sucralose; (vii) about 1 mg/mL ofsodium methyl parahydroxybenzoate; and (viii) about 0.6 mg/mL of sodiumethyl parahydroxybenzoate.
 21. The pharmaceutical composition of claim1, comprising: (i) about 40 mg/mL of Ibrutinib; (ii) about 14 mg/mL ofmicrocrystalline cellulose and carboxymethylcellulose sodium; (iii)about 1 mg/mL of hydroxypropylmethylcellulose; (iv) about 1.6 mg/mL ofcitric acid monohydrate; (v) about 1.4 mg/mL of disodium hydrogenphosphate; (vi) about 0.5 mg/mL of sucralose; (vii) about 1.4 mg/mL ofsodium methyl parahydroxybenzoate; and (viii) about 0.7 mg/mL of sodiumethyl parahydroxybenzoate.
 22. A method for treating a B-cellproliferative disorder comprising administering a pharmaceuticalcomposition of claim 1 to a subject in need thereof.
 23. The method ofclaim 22, wherein said B-cell proliferative disorder is a non-Hodgkinlymphoma, Waldenstrom macroglobulinemia, plasma cell myeloma, or chroniclymphocytic leukemia.
 24. The method of claim 23, wherein thenon-Hodgkin lymphoma is selected from the group consisting of diffuselarge B cell lymphoma, follicular lymphoma, mantle cell lymphoma andburkitt lymphoma.
 25. The method of claim 22, wherein the composition isadministered orally.
 26. A method for treating a lymphoma comprisingadministering a composition of claim 1 to a subject in need thereof. 27.A method of treating a leukemia, said method comprising administering acomposition of claim 1 to a subject in need thereof.
 28. A method fortreating mantle cell lymphoma in a subject who has already received atleast one prior therapy for mantle cell lymphoma, said method comprisingadministering to the subject a composition of claim 1 once per day. 29.The method of claim 1, wherein the subject is a human.
 30. The method ofclaim 1, wherein the composition is scattered into food.
 31. The methodof claim 30, wherein the food is soft food.
 32. The method of claim 31,wherein the subject is a human child.
 33. A process for preparing acomposition of claim 1, said process comprising: (a) mixing water,microcrystalline cellulose croscarmellose sodium; (b) mixing water andwith hydroxypropylmethylcellulose; (c) mixing the product of step (b)with Ibrutinib; (d) mixing the product of steps (a) and (c); (e) mixingthe product of step (d) with sucralose; (f) mixing the product of step(e) with sodium methyl parahydroxybenzoate and sodium ethylparahydroxybenzoate; (g) mixing the product of step (f) with monohydratecitric acid; and (h) mixing the product of step (g) with anhydrousdisodium hydrogen phosphate.